The present invention is directed to a process for the preparation of the stable, amorphous calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the formula V.
The present invention is also directed to a process for the preparation of stable, crystalline (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the formula IV.
The present invention is also directed to a process for the preparation of an aqueous solution of the calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydro-folic acid of the formula III.
In the present invention for 5,6,7,8-tetra-hydrofolic acid is used sometimes the abbreviation THF.
A short summary concerning the pharmacological importance of N(5)-methyl-5,6,7,8-tetrahydrofolic acid—herein sometimes abbreviated with N(5)-methyl-THF—and derivatives thereof is given in the beginning of the description of EP 0 455 013 A1. In the same document is also pointed to the importance of the individual (6S)- and (6R)-diastereoisomers of N(5)-methyl-THF. Herein is also described the prior art concerning the preparation of the pure (6S)- and (6R)-diastereoisomers of N(5)-methyl-THF.
In EP 1 044 975 A1 are described stable crystalline salts of N(5)-methyl-THF. Herein are also described crystalline calcium salts of (6S)-N(5)-methyl-THF, whereby these salts have in the respective X-ray powder diffraction diagram well defined 2-Theta-values.
In the preparation process of these salts are used as starting materials either the mixture of the (6RS)-diastereoisomers or the already separated (6S)- or (6R)-diastereoisomers. This process involves a temperature treatment of more than 60° C., preferably of more than 85° C., whereby in the working examples are mentioned temperatures from 90° C. to 100° C.
Such a temperature treatment is of course less suitable for an industrial preparation of these salts.
In EP 1 044 975 A1 is not mentioned by what way the individual (6S)- or (6R)-diastereoisomers of N(5)-methyl-THF were obtained.